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Mitochondrial metabolism is an attractive target for cancer therapy 1 , 2 . Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC) 1 , 3 . Here we show that BTB and CNC homology1 (BACH1) 4 , a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin 5 , 6 , suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours 7 . Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors. The transcription factor BACH1, which targets mitochondrial metabolism, is expressed at high levels in several types of cancer; reducing its expression in tumours makes them more susceptible to treatment with mitochondrial inhibitors.

Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)—a master transcriptional regulator of lysosomal biogenesis and autophagy—is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.Nakamura et al. find that the master transcriptional regulator of lysosomal biogenesis and autophagy TFEB is activated following LC3 lipidation during lysosomal damage and show the importance of this mechanism during kidney injury.

The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates 1 – 3 . However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy 4 , 5 , is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases. Owing to this mechanism, the phosphorylation of TFEB—unlike other substrates of mTORC1, such as S6K and 4E-BP1— is strictly dependent on the amino-acid-mediated activation of RagC and RagD GTPases, but is insensitive to RHEB activity induced by growth factors. This mechanism has a crucial role in Birt–Hogg–Dubé syndrome, a disorder that is caused by mutations in the RagC and RagD activator folliculin ( FLCN ) and is characterized by benign skin tumours, lung and kidney cysts and renal cell carcinoma 6 , 7 . We found that constitutive activation of TFEB is the main driver of the kidney abnormalities and mTORC1 hyperactivity in a mouse model of Birt–Hogg–Dubé syndrome. Accordingly, depletion of TFEB in kidneys of these mice fully rescued the disease phenotype and associated lethality, and normalized mTORC1 activity. Our findings identify a mechanism that enables differential phosphorylation of mTORC1 substrates, the dysregulation of which leads to kidney cysts and cancer. Dysregulation of an mTORC1 substrate-specific mechanism leads to constitutive activation of TFEB, and promotes kidney cystogenesis and tumorigenesis in a mouse model of Birt–Hogg–Dubé syndrome.

The Arabidopsis basic region-leucine zipper transcription factor 11 (bZIP11) is known to be repressed by sucrose through a translational inhibition mechanism that requires the conserved sucrose control peptide encoded by the mRNA leader. The function of bZIP11 has been investigated in over-expression studies, and bZIP11 has been found to inhibit plant growth. The addition of sugar does not rescue the growth inhibition phenotype. Here, the function of the bZIP11 transcription factor was investigated. The mechanism by which bZIP11 regulates growth was studied using large-scale and dedicated metabolic analysis, biochemical assays and molecular studies. bZIP11 induction results in a reprogramming of metabolism and activation of genes involved in the metabolism of trehalose and other minor carbohydrates such as myo-inositol and raffinose. bZIP11 induction leads to reduced contents of the prominent growth regulatory molecule trehalose 6-phosphate (T6P). The metabolic changes detected mimic in part those observed in carbon-starved plants. It is proposed that bZIP11 is a powerful regulator of carbohydrate metabolism that functions in a growth regulatory network that includes T6P and the sucrose non-fermenting-1 related protein kinase 1 (SnRK1).

OsbZIP23 is a member of the basic leucine zipper (bZIP) transcription factor family in rice (Oryza sativa). Expression of OsbZIP23 is strongly induced by a wide spectrum of stresses, including drought, salt, abscisic acid (ABA), and polyethylene glycol treatments, while other stress-responsive genes of this family are slightly induced only by one or two of the stresses. Transactivation assay in yeast demonstrated that OsbZIP23 functions as a transcriptional activator, and the sequences at the N terminus (amino acids 1-59) and a region close to the C terminus (amino acids 210-240) are required for the transactivation activity. Transient expression of OsbZIP23-green fluorescent protein in onion (Allium cepa) cells revealed a nuclear localization of the protein. Transgenic rice overexpressing OsbZIP23 showed significantly improved tolerance to drought and high-salinity stresses and sensitivity to ABA. On the other hand, a null mutant of this gene showed significantly decreased sensitivity to a high concentration of ABA and decreased tolerance to high-salinity and drought stress, and this phenotype can be complemented by transforming the OsbZIP23 back into the mutant. GeneChip and real-time polymerase chain reaction analyses revealed that hundreds of genes were up- or down-regulated in the rice plants overexpressing OsbZIP23. More than half of these genes have been annotated or evidenced for their diverse functions in stress response or tolerance. In addition, more than 30 genes that are possible OsbZIP23-specific target genes were identified based on the comparison of the expression profiles in the overexpressor and the mutant of OsbZIP23. Collectively, these results indicate that OsbZIP23 functions as a transcriptional regulator that can regulate the expression of a wide spectrum of stress-related genes in response to abiotic stresses through an ABA-dependent regulation pathway. We propose that OsbZIP23 is a major player of the bZIP family in rice for conferring ABA-dependent drought and salinity tolerance and has high potential usefulness in genetic improvement of stress tolerance.

Basic leucine zipper transcription factors (bZIP TFs) play important roles in the ABA signaling pathway in plants. Rice OsbZIP42 is a member of the group E bZIP, which is an ortholog of Arabidopsis group A bZIP. This latter group includes abscisic acid-responsive element (ABRE)-binding factors (ABFs) involved in abiotic stress tolerance. The expression of OsbZIP42 was induced by ABA treatment, although it was not induced by drought and salt stresses. Unlike other bZIP TFs, OsbZIP42 contained two transcriptional activation domains. Although the full-length OsbZIP42 protein did not, the N-terminus of the protein interacted with SAPK4. Our results suggest that the activation of OsbZIP42 by SAPK4 requires another ABA-dependent modification of OsbZIP42. Transgenic rice overexpressing OsbZIP42 (OsbZIP42-OX) exhibited a rapidly elevated expression of the ABA-responsive LEA3 and Rab16 genes and was hypersensitive to ABA. Analyses of the OsbZIP42-OX plants revealed enhanced tolerance to drought stress. These results suggest that OsbZIP42 is a positive regulator of ABA signaling and drought stress tolerance depending on its activation, which is followed by an additional ABA-dependent modification. We propose that OsbZIP42 is an important player in rice for conferring ABA-dependent drought tolerance.

In plants, the bZIP (basic leucine zipper) transcription factors regulate diverse functions, including processes such as plant development and stress response. However, few have been functionally characterized in maize (Zea mays). In this study, we cloned ZmbZIP72, a bZIP transcription factor gene from maize, which had only one copy in the maize genome and harbored three introns. Analysis of the amino acid sequence of Zmb-ZIP72 revealed a highly conserved bZIP DNA-binding domain in its C-terminal region, and four conserved sequences distributed in N- or C-terminal region. The ZmbZIP72 gene expressed differentially in various organs of maize plants and was induced by abscisic acid, high salinity, and drought treatment in seedlings. Subcellular localization analysis in onion epidermal cells indicated that ZmbZIP72 was a nuclear protein. Transactivation assay in yeast demonstrated that ZmbZIP72 functioned as a transcriptional activator and its N terminus (amino acids 23-63) was necessary for the transactivation activity. Heterologous overexpression of ZmbZIP72 improved drought and partial salt tolerance of transgenic Arabidopsis plants, as determined by physiological analyses of leaf water loss, electrolyte leakage, proline content, and survival rate under stress. In addition, the seeds of Zmb-ZIP72-overexpressing transgenic plants were hypersensitive to ABA and osmotic stress. Moreover, overexpression of ZmbZIP72 enhanced the expression of ABA-inducible genes such as RD29B, RAB18, and HIS1-3. These results suggest that the ZmbZIP72 protein functions as an ABA-dependent transcription factor in positive modulation of abiotic stress tolerance and may be a candidate gene with potential application in molecular breeding to enhance stress tolerance in crops.

The AP1 transcription factor Batf3 is required for homeostatic development of CD8α + classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3 -independent pathway in mice for CD8α + dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf , which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines. The roles of BATF transcription factors in dendritic cell differentiation are studied, providing evidence for molecular compensation by related family members; compensation is based on the interaction of the BATF leucine zipper domains with IRF factors to mediate cooperative gene activation. Immune responses linked to BATF–IRF4 Kenneth Murphy and colleagues study the roles of the AP-1 transcription factor BATF in dendritic-cell differentiation — a process that primes CD8 + T-cell responses to intracellular pathogens — and provide evidence for molecular compensation by related family members. Compensation is based on the interaction of the BATF leucine-zipper domains with the interferon regulatory factors IRF4 and IRF8 to mediate cooperative gene activation. In a complementary study, Warren Leonard and colleagues provide evidence that IRF4 regulates CD4 + T-cell differentiation and T H 17 function by cooperative binding interactions with the AP-1 family members BATF and JUN. These studies point to potential new targets for manipulating key immune responses that depend on BATF–IRF4 interactions.

Key Points BTB and CNC homology (BACH) proteins are transcriptional repressors of the basic region leucine zipper (bZIP) transcription factor family. BACH proteins have widespread roles in immunological processes, including tolerance, memory, immunosuppression and iron homeostasis. BACH proteins stabilize lineage commitment and promote cell-type-specific functions through the repression of alternative lineage programmes. Competitive interactions with transcriptional activators of the bZIP family form a common mechanistic theme underlying the diverse functions of BACH factors. The expression and function of BACH factors are regulated by extrinsic signals to enable fine-tuning of cellular functions. The transcriptional repressors BTB and CNC homology 1 (BACH1) and BACH2 compete with transcriptional activators of the basic region leucine zipper (bZIP) family to control widespread functions of the innate and adaptive immune systems. BTB and CNC homology (BACH) proteins are transcriptional repressors of the basic region leucine zipper (bZIP) transcription factor family. Recent studies indicate widespread roles of BACH proteins in controlling the development and function of the innate and adaptive immune systems, including the differentiation of effector and memory cells of the B and T cell lineages, CD4 + regulatory T cells and macrophages. Here, we emphasize similarities at a molecular level in the cell-type-specific activities of BACH factors, proposing that competitive interactions of BACH proteins with transcriptional activators of the bZIP family form a common mechanistic theme underlying their diverse actions. The findings contribute to a general understanding of how transcriptional repressors shape lineage commitment and cell-type-specific functions through repression of alternative lineage programmes.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the loss of nigrostriatal dopaminergic neurons. Mounting evidence suggests that Nrf2 is a promising target for neuroprotective interventions in PD. However, electrophilic chemical properties of the canonical Nrf2-based drugs cause irreversible alkylation of cysteine residues on cellular proteins resulting in side effects. Bach1 is a known transcriptional repressor of the Nrf2 pathway. We report that Bach1 levels are up-regulated in PD postmortem brains and preclinical models. Bach1 knockout (KO) mice were protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity and associated oxidative damage and neuroinflammation. Functional genomic analysis demonstrated that the neuroprotective effects in Bach1 KO mice was due to up-regulation of Bach1-targeted pathways that are associated with both Nrf2-dependent antioxidant response element (ARE) and Nrf2-independent non-ARE genes. Using a proprietary translational technology platform, a drug library screen identified a substituted benzimidazole as a Bach1 inhibitor that was validated as a nonelectrophile. Oral administration of the Bach1 inhibitor attenuated MPTP neurotoxicity in pre- and posttreatment paradigms. Bach1 inhibitor–induced neuroprotection was associated with the up-regulation of Bach1-targeted pathways in concurrence with the results from Bach1 KO mice. Our results suggest that genetic deletion as well as pharmacologic inhibition of Bach1 by a nonelectrophilic inhibitor is a promising therapeutic approach for PD.